Accepted Manuscript

Formulation and evaluation of 4-benzylpiperidine drug-in-adhesive matrix type

transdermal patch

Sindhu S. Ganti, Sonalika A. Bhattaccharjee, Kevin S. Murnane, Bruce E.

Blough, Ajay K. Banga

PII: S0378-5173(18)30611-2
DOI: https://doi.org/10.1016/j.ijpharm.2018.08.033
Reference: IJP 17718

To appear in: International Journal of Pharmaceutics

Received Date: 23 March 2018

Revised Date: 2 June 2018
Accepted Date: 16 August 2018

Please cite this article as: S.S. Ganti, S.A. Bhattaccharjee, K.S. Murnane, B.E. Blough, A.K. Banga, Formulation
and evaluation of 4-benzylpiperidine drug-in-adhesive matrix type transdermal patch, International Journal of
Pharmaceutics (2018), doi: https://doi.org/10.1016/j.ijpharm.2018.08.033

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4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 1

Formulation and evaluation of 4-benzylpiperidine drug-in-

adhesive matrix type transdermal patch

Sindhu S. Ganti1*, Sonalika A. Bhattaccharjee1*, Kevin S. Murnane1, Bruce E. Blough2,

Ajay K. Banga1#

1
Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta,
GA 30341
2
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC,
27709, USA

* Both authors contributed equally

#
To whom correspondence should be addressed

E-mail: Banga_ak@mercer.edu
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 2

ABSTRACT

The objective of our study was to develop a transdermal patch of 4-benzylpiperidine and to evaluate

its in vitro transdermal permeation profile. Appropriate pressure sensitive adhesives and additives were

selected based on solubility and slide crystallization studies. Release liners and backing membranes were

selected based on their ability to peel without leaving a residue and their affinity to formulation respectively.

Drug-in-adhesive patches developed were investigate for their in vitro drug permeation over 48 hours across

dermatomed human skin using Franz diffusion cells. Silicone based pressure sensitive adhesive along with

colloidal silicon dioxide as viscosity builder, fluoropolymer coated membranes as the release liner and

polyester based membranes as backing were chosen to develop a drug in silicone adhesive patch.

Polyisobutylene adhesive based patch was developed with drug in polyisobutylene adhesive, along with

oleic acid and oleyl alcohol as permeation enhancers, polyester for the release liner and polyethylene as

backing. Among the patches developed, polyisobutylene adhesive based patch with higher drug

concentration exhibited superior transdermal permeation (1608.5  53.4 µg/cm2 over 48 hrs.). The final

patch was further tested for uniformity in coat weight, shear strength, tack and peel adhesion.

KEY WORDS: Transdermal patch, 4-benzylpiperidine, in vitro permeation, silicone adhesive,

polyisobutylene adhesive, substitute agonist

ABBREVIATIONS

ADHD Attention-deficit/hyperactivity disorder

ANOVA Analysis of variance
PBS Phosphate buffered saline
PIB Polyisobutylene
PSA Pressure sensitive adhesives
RP-HPLC Reverse phase high performance liquid chromatography
SE Standard error
TDDS Transdermal drug delivery systems
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 3

1. Introduction

Cocaine remains one of the most used illicit drugs worldwide with an estimated 17 million users in

2015, making it a major public health issue (United Nations publication, 2017). Despite its negative health

consequences and addictive potential, there is no FDA-approved pharmacotherapies (Vocci et al., 2005;

Vocci and Appel, 2007; Volkow and Li, 2004). Another such major public health issue with an estimated

worldwide occurrence of about 5% in children (Polanczyk et al., 2014), and symptoms that continue into

adulthood in up to 65% of patients (Faraone et al., 2006), is attention-deficit/hyperactivity disorder (ADHD).

The incidence of adult ADHD appears to be much higher in individuals with cocaine-use disorder,

compared to the general population. In a sample of adult patients seeking treatment for cocaine addiction,

35% were found to have ADHD. These numbers are in line with the assumption that adolescents with

ADHD are about twice as likely as healthy individuals to develop a substance use disorder due to the impact

of neurotransmitter systems in the brain thought to be altered in ADHD patients (Wunderli et al., 2016).

Substitute-agonist therapies mimic key aspects of the abused drug to reduce craving and withdrawal

and promote abstinence (Herin et al., 2010). Research over the last decade has suggested that substitute

agonist-based strategy can be useful in treating cocaine-use disorders (Mariani and Levin, 2007; Rothman,

2005). Chronic cocaine abuse is believed to result in depletion of dopamine. Dopamine deficiency has also

been associated with ADHD in adults, and dopamine agonists have been effective in the pharmacotherapy

of ADHD. Bromocriptine, a dopamine agonist was highly effective for treating ADHD and promoting

cocaine abstinence (Grabowski et al., 2004). While the exact etiology of ADHD remains unknown, the

available evidence supports the theory that dopamine neurotransmission dysfunction is at least partly

responsible for its characteristic symptoms (Cocores et al., 1987).

Previously FDA has approved substitute-agonist therapies for substance-use disorders including

methadone, buprenorphine, varenicline, and transdermal and buccal formulations of nicotine. Additionally,

methylphenidate transdermal patch (Daytrana) has been successfully used for the treatment of ADHD

(Mariani and Levin, 2007). It was the relative success of these medications for treatment of substance-use

that stimulated initial research on potential of agonist medications to treat cocaine dependence (Silver,
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 4

2017). While there are currently no FDA-approved medications for cocaine dependence, agents that reverse

dopamine transporter activity and boost dopamine transmission like amphetamines have shown promise.

Dextroamphetamine and methamphetamine have shown to reduce cocaine use in patients with cocaine

dependence alone, and mixed amphetamine salts have shown to reduce cocaine use in co-occurring cocaine

dependence and ADHD. Dextroamphetamine and mixed amphetamine salts are FDA-approved treatments

for ADHD, and are believed to work by boosting dopamine levels in the forebrain (Negus and Henningfield,

2014). Given these findings, we know both the disorders are linked to dopamine deficiency and can benefit

from treatment with dopamine substitute agonists.

Although many targets for cocaine-use disorder have been identified, substitute agonists that

function as substrate-based dopamine/norepinephrine releasers have demonstrated promising efficacy in

preclinical models and double-blind placebo controlled clinical trials (Grabowski et al., 2004). 4-

benzylpiperidine is one such substrate-based dopamine/norepinephrine releasing substitute-agonist to

cocaine with distinguished preclinical efficacy but has rapid onset of action and short duration of action.

The value of an agonist medication lie in its ability to target pharmacological receptors to produce effects

for a long duration of time with slower onset, and thereby, reducing cravings for drug of abuse while

ensuring lower toxicity than produced by use of the abused drug. It is therefore critical to sustain the

duration of action of 4-benzylpiperdine. Transdermal patches can provide this much needed slow and

sustained delivery of 4-benzylpiperidine. Slow drug onset can reduce abuse potential, promote abstinence

and prolonged duration of action can reduce the frequency of dosing leading to better compliance and

reduce problematic neuroadaptations to the severe oscillations in drug levels that often occur with drug

abuse. Further, transdermal patches can be abuse deterrent as it is harder and more time consuming to

extract drug over conventional dosage forms (Puri et al., 2017).

Considering the prominent preclinical efficacy of 4-benzylpiperidine in human-relevant animal

models and the therapeutic benefits of transdermal drug delivery of substitute agonists for cocaine-use

disorder and ADHD, the aim of our study was to develop a drug-in-adhesive matrix transdermal patch of
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 5

4-benzylpiperidine. The objective was extended to evaluate the transdermal matrix patch based on the in

vitro drug permeation profile across dermatomed human skin, and adhesion properties of the patch.

2. Materials and methods

2.1. Materials

4-Benzylpiperidine was obtained from Sigma Aldrich (St. Louis, MO, USA). Acetonitrile, methanol,

tetrahydrofuran and Phosphate Buffered Saline (PBS) were purchased from Fisher Scientific (NJ, USA).

Acrylate PSA (DURO-TAK 87-2516 and DURO-TAK 87-2287) as well as PIB adhesive (DURO-TAK 87-

6908) were obtained as gift samples from Henkel Corporation (Dusseldorf, Germany). Silicone adhesive

(BIO-PSA 7-4301) was also provided as gift sample by Dow Corning Corporation (Washington, DC, USA).

Backing membranes (CoTranTM 9707, CoTranTM 9702, CoTranTM 9722, CoTranTM 9706, CoTranTM 9718 and

ScotchPak 9723) and release liners (ScotchPak 9741) were

TM TM TM TM
9744, ScotchPak 1022 and ScotchPak

gifted by 3M (St. Paul, MN, USA). Isopropyl myristate, colloidal silicone dioxide, oleic acid, olely alcohol,

propylene glycol and mineral oil were purchased from Sigma Aldrich (St. Louis, MO, USA). Dermatomed

human skin was obtained from New York firefighters skin bank (New York, NY).

2.2. Methods

2.2.1. Development of transdermal patch

The choice of pressure sensitive adhesives (PSAs), release liner and backing membrane is critical

for the development of a transdermal patch and were investigated extensively for the development of a 4-

benzypiperidine drug-in-adhesive matrix transdermal patch.

2.2.1.1. Selection of PSA

Currently there are three types of pressure sensitive bioadhesive polymers commonly used in the

United States transdermal drug delivery market: polyacrylate copolymers (acrylates), polysiloxanes
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 6

(silicones) and polyisobutylenes (PIBs) (Kandavilli et al., 2002; Tan and Pfister, 1999). In our study, the

feasibility of employing acrylate (DURO-TAK 387-2287 and DURO-TAK 387-2516), silicone (BIO PSA

7-4301) and PIB (DURO-TAK 87-6908) adhesives for the formulation of 4-benzylpiperidine drug-in-

adhesive transdermal patches was tested. Slide crystallization studies were performed to identify the drug

concentration at which the drug crystallizes or separates out. The highest concentration at which the drug

remained dissolved, was considered as the drug's saturation solubility in each adhesive. Formulations with

increasing concentrations of drug (% w/w) in adhesive were prepared (as presented in Table 1 and 2) and

allowed 48 hours of slow mixing at room temperature using a rotary mixer (Preiser Scientific Inc., St.

Albans, WV, USA). Following visual observation, a drop of each formulation blend was placed on

individual polysine microscopic slides (25 x 75 x1 mm, Thermo scientific, Erie scientific, New Hampshire,

U.S.A) and dried under a fume hood at room temperature, followed by examination under an optical light

microscope (Leica DM 750; Buffalo Grove, IL). Images were taken at 10× or 100× magnification (as

specified) using a DFC-280 camera adjoining the microscope.

2.2.1.2. Selection of additives

Penetration enhancers were explored to facilitate the delivery of 4-benzylpiperidine across skin and

increase its solubility in the adhesives. The physical and chemical compatibility of isopropyl myristate,

oleic acid, olely alcohol and mineral oil with the drug as well as the adhesives were tested. To determine

the solubility of 4-benzylpiperidine in the enhancers, increasing amounts of 4-benzylpiperidine was added

to the individual penetration enhancers, followed by mixing for 48 hours in a rotary mixer. The solubility

and stability of the enhancers in the adhesives were determined similarly, by adding increasing amounts of

the enhancers to the adhesives, followed by mixing for 48 hours in a rotary mixer. The adhesive blends

were applied to individual polysine microscopic slides, dried under a fume hood at room temperature, and

observed under an optical light microscope.

In addition, colloidal silicon dioxide was explored as a viscosity builder, and first homogenized to

a gel with heptane using a high-speed homogenizer (OmniTHQ, Omni International, NW, GA, USA) at
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 7

32000 rpm for 10 min. Varying concentrations of the gel, corresponding to the amount of colloidal silicon

dioxide, were then added to the drug in silicone formulations (presented in Table 3), followed by evaluation

with slide crystallization studies.

2.2.1.3. Selection of release liner and backing membrane

The following commonly used release liners: ScotchPakTM 9744, ScotchPakTM 1022 and

ScotchPakTM 9741 and backing membranes: CoTranTM 9707, CoTranTM 9702, CoTranTM 9722, CoTranTM

9706, CoTranTM 9718 and ScotchPakTM 9723, were evaluated (Kandavilli et al., 2002). Combinations of the

release liners and backing films were tested with the final drug-in-adhesive formulation blends (F-C-11, F-

C-12, 10POA and 15POAOH). Initial screening was performed by checking the affinity of the formulations

for both sides of each membrane, by adding a drop of the formulation on the membranes, followed by

drying in a fume hood to evaporate the adhesive solvent. A gloved hand was used to test the peeling and

adhesiveness of the formulations on individual membranes.

2.2.2. Drug in adhesive patch preparation

The drug in adhesive transdermal patches were prepared by dissolving pre-determined amounts of drug,

adhesive, and additives (presented in Table 5) into an air-tight glass vial (20-mL capacity) and stirred for

24 hours using a rotary mixer. For the silicone adhesive based formulations, colloidal silicon dioxide was

first homogenized into a gel as previously discussed, followed by the addition of the drug and the adhesive,

which was then homogenized using a high shear homogenizer at 1200 rpm for 15 minutes. The silicone and

PIB formulations were cast on individual release liners using a Gardner film casting knife (BYK-AG-4300

series, Columbia, MD, USA) and dried. The compositions, casting parameters, release liner, backing

membrane, and drying conditions employed for the formulation of different patches have been elaborated

in Table 5. Following drying, the sheets were laminated using individual backing membranes, which were

placed on the cast films using a roller, ensuring no air pockets were formed. These laminated films were

then die cut into drug in adhesive matrix transdermal patches of 2.83 cm2. The patches were stored at room
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 8

temperature for two weeks and observed under an optical light microscope. Visual changes including phase

separation, contraction/shrinkage of the film, residue on release liner after peeling and ease of peeling off

the patches were noted as well. Laminates without crystals and phase separation, with good physiochemical

properties, were used for in vitro permeation studies on dermatomed human skin.

2.2.3. In vitro permeation

2.2.3.1. Skin preparation

Human dermatomed skin was stored at -80°C and thawed before use in 10 mM PBS (pH 7.4) at

37 °C for 2 mins. After thawing, skin was cut into pieces of appropriate sizes and their thickness was

measured using a digital micrometer (Electronic Equip’t Co. Inc, Cedarhurst, NY, USA). Skin pieces with

comparable thickness values were used for further skin integrity studies.

2.2.3.2. Skin integrity testing

The barrier integrity of human dermatomed skin was evaluated by skin electrical resistance

assessment. In this study, prepared skin pieces of appropriate thickness were clamped between the donor

compartment containing 300 µL of 10 mM PBS and receptor compartment containing 5 ml of 10 mM PBS

of a vertical Franz diffusion cell setup and allowed to equilibrate for 15 min. Silver chloride wire (load

resistor RL) was dipped in the donor chamber and silver electrode immersed in the receptor compartment.

Skin resistance was measured by passing a constant current (voltage of 100 mV AC electrical field at 10

Hz, duty cycle 50% without offset) through skin using a Digital Multimeter (Agilent 34410A 61/2 Digit)

and Function/Arbitrary waveform generator (Agilent 33220A 20 MHz, Agilent Technologies, CA, USA).

The voltage across the skin (Vs) was displayed on the multimeter and electrical resistance values were

calculated using equation I.

𝑉𝑆 𝑅𝐿
𝑅𝑠 = (𝑉0 −𝑉𝑆 )
(Eq I)

Where,
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 9

RS represents skin electrical resistance (kΩ)

VS represents the voltage drop across the skin (mV)

VO represents the voltage drop across the whole circuit (100 mV)

RL represents the load resistance (100 kΩ)

Skin pieces with resistance greater than 4 kΩ were selected for the studies. The resistance of all

skin pieces chosen for the study ranged between 4-17 kΩ.

2.2.3.3. In vitro permeation studies using optimized patches

In vitro transdermal permeation studies were performed to evaluate the performance of the drug-

in-adhesive transdermal patches, based on the amount of drug that permeates across human dermatomed

skin over 48 hours using vertical Franz diffusion cells (PermeGear V6 station vertical cell). Three different

matrix transdermal patches (S1, P1 and P2) with four replicates (n=4) were tested for their in vitro

transdermal permeation performance. Transdermal patches, large enough to cover the Franz cells were

punched using a die and the release liner was removed. The patches were placed on the skin, dried using

kim wipes, such that the adhesive side of the patch was in contact with the stratum corneum of the skin. A

glass rod with minimal pressure was rolled over the patch to ensure the patch is in complete contact with

the skin. The skin with the matrix patch was immediately placed over the surface of the receptor

compartment, followed by clamping of skin with patch between the donor compartment and receptor

compartment. The receptor comprised of 10 mM PBS (pH 7.4) maintained at 37 °C and constantly stirred

at 600 rpm. The donor chamber was exposed to room temperature (25 °C) to attain a skin temperature of

32 °C. Samples (300 µL) were withdrawn from the receptor compartment at zero time, 1 h, 2 h, 4 h, 6 h, 8

h, 24 h and 48 h and quantified using RP-HPLC (reverse phase high performance liquid chromatography).

Equal amount of 10 mM PBS (pH 7.4) was replenished in the receptors.

4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 10

2.2.3.4. HPLC quantification

A RP-HPLC Waters 2695 Separation Module attached to a Waters 2996 photodiode array detector

connected to a prodigy 5 µ ODS (150 mm length x 4.60 mm diameter, 5-micron particle size) column were

used for the quantitative analysis of 4-benzylpiperdine. Acetonitrile and deionized water (0.05% v/v TFA)

in gradient mode and flow rate of 1.0 mL/min were employed as the mobile phase. The percentage of

acetonitrile was increased from 10% to 80% from 0 to 8 min, then kept at 80% till 13 min, followed by a

decrease to 10% at 13.01 min and maintained at 10% till 15 min (end of the run). 4-Benzylpiperidine was

detected at 259 nm wavelength with a retention time of 5.5 min.

2.2.3.5. Data analyses

All values have been presented as mean ± SE. One-way ANOVA was performed to investigate

significant difference between groups. Statistically significant difference was shown by p values < 0.05.

2.2.4. Characterization of the optimized drug in adhesive patch

The transdermal matrix patch that exhibited the highest drug permeation across dermatomed human

skin in 48 hours was elected as the final patch and further characterized.

2.2.4.1. Determination of coat weight

The coat weight of the drug in adhesive patch was determined by punching (using a die cut) and

weighing 0.28 cm2 of the laminates (adhesive matrix with backing membrane and release liner) and

subtracting the weight of the backing membrane and release liner (n=6). The average weight of the patch

along with the standard error was reported.

2.2.4.2. Peel adhesion test

The bond strength of the optimized patch (P2) was determined using a PA-1000-180 180◦ peel

adhesion tester (Chem Instruments, Fairfield, OH, USA). The force required to pull the patch away from a
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 11

non-flexible material (stainless steel), that is positioned parallel to the patch, was quantified. The instrument

was calibrated prior to use and setup at a speed of 30 cm/min and a peel length of 0.5. Rectangular strips

of the patch were cut to the size of 6.35 x 1.5 cm (n = 6) and used for this test. One end of the test strip was

placed in the load cell grip and the other end was made to adhere to the test platform. The average force

required to peel the patch from the stainless steel was determined and recorded.

2.2.4.3. Shear strength

Sheer strength of the patch was tested using a SS-HT-8 High Temperature 8 Bank Shear Tester

(Chem Instruments, Fairfield, OH, USA). All patches were cut into 2 cm wide and 8 cm long strips. The

liner was removed from one end and patch was applied on the test panel of shear tester such that 5 cm long

strip is stuck on to the test panel with a 3 cm attaching length. The other end was attached with hooks and

weight (500 g) was applied on the hook. The time required for the patch to fall was recorded and repeated

for six replicates.

2.2.4.4. Tack Testing

A TA.XTPlus Texture Analyzer (TTC, Hamilton, Massachusetts, USA) was used to determine the

tack value of the final drug-in-adhesive patch, P2. The texture analyzer was calibrated for weight, height,

and a distance of 50 mm. The patch was cut to an appropriate size and the release liner was removed such

that the adhesive part of the patch could be stuck onto the TA-303 Indexable Tack Rig with ten 9 mm

openings. The stainless-steel probe was then lowered into the 9 mm openings of the indexable tack rig and

a constant force of 0.05 N was applied onto the sample for 5 seconds and, finally, the probe was removed

with a constant rate. The debonding velocity (Vd) was set to 5 mm/s. The absence of PSA residues from

the stainless-steel surface of the probes (adhesive failure) was visually determined. The absolute positive

force required for debonding is recorded along with the positive area and separation distance. Exponent

texture analysis software was used to measure the detachment force (absolute positive force) and the
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 12

elongation at break (separation distance) expressed in grams and millimeters, respectively. The results are

expressed as the mean ± standard error (n = 6).

3. Results and Discussion

3.1. Development of the transdermal patch

Transdermal drug delivery systems (TDDS) are employed for the delivery of drugs across skin,

into the systemic circulation. Adhesion of a TDDS to skin is a critical factor that affects its performance.

The entire delivery surface of a TDDS must be in complete contact with skin, as the partitioning of the drug

between the TDDS and skin is the driving force for permeation. In transdermal patches, the adhesiveness

of the PSA helps maintain this intimate contact with skin. Apart from adhesion, the PSA also affects other

critical quality attributes of the TDDS such as drug delivery, flux across skin and physical and chemical

stability, making it critical to the safety, efficacy and quality of the finished product. The selection of a

suitable PSA is thus pivotal in the development of a transdermal patch (Deepthi and Khan, 2012; Lobo et

al., 2016). In our study we employed solubility and crystallization studies to aid us choose the most

appropriate PSA for our drug.

The three most commonly used PSAs i.e. acrylates, silicone and PIB base adhesives were all used

in this study. Initial blends prepared (as presented in Table 1) were observed visually, indicating that the

solubility of 4-benzylpiperidine was the highest in the acrylate adhesives (greater than 20% w/w in DURO-

TAK 387-2516 and greater than 10% w/w in DURO-TAK 387-2287). However, color change in the soluble

blends indicative of degradation or incompatibility of 4-benzylpiperidine as well as formation of crystals

on drying with the acrylate adhesives was observed (presented in Fig. 1). Hence, further studies using the

acrylate PSAs were discontinued.

The solubility of 4-benzylpiperidine in silicone and PIB adhesives was found to be lower than 5%

w/w. Blends were prepared in accordance to Table 2, and the solubility of 4-benzylpiperidine in silicone

and PIB was found to be less than 4.5% w/w. Slide crystallization was used as a preliminary and relatively

fast screening tool to mimic the nature of the final casted laminate and the interaction between the drug and
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 13

adhesive in the final product. It was employed as an alternative to preparing complete patches (Jain and

Banga, 2013). These studies revealed no crystal formation, degradation, or separation over time in the drug

in PIB blends (4.5 %, 3 %, 2 % w/w drug). Thus, PIB was further developed into a transdermal patch of 4-

benzylpiperidine. Slide crystallization studies in all the blends prepared with silicone adhesive showed

separation of the 4-benzylpiperidine from the dried silicone matrix (shown in Fig. 1). However, as no

degradation of 4-benzylpiperidine or any physical incompatibility in terms of color change or the formation

of crystals was observed, silicone PSA was also further explored for the development of the 4-

benzylpiperidine transdermal patch.

In our study, permeation enhancers were explored to prevent phase separation observed in drug in

silicone formulations, increase the solubility of drug in both silicone and PIB PSAs to allow more drug

loading into the patch, and subsequently increase the penetration of drug across skin. Isopropyl myristate,

propylene glycol, mineral oil, oleic acid and olelyl alcohol were evaluated, as 4-benzylpiperidine was found

to be the most soluble in these enhancers after an initial preliminary screening of commonly used

permeation enhancers. Preliminary screening involved adding increasing amounts of the permeation

enhancers to the drug and adhesives blends, followed by visual and microscopic observation. Among these,

isopropyl myristate showed higher miscibility with silicone PSA, while oleic acid and olelyl alcohol were

better miscible with PIB PSA. Consequently, isopropyl myristate was tested as a solubility and penetration

enhancer for the drug in silicone blends whereas, oleic acid and olely alcohol were incorporated in the drug-

in-PIB blends.

Silicone adhesive blends with isopropyl myristate (5% and 10% w/w) and increasing

concentrations of 4-benzylpiperidine (5%, 10% and 12.5% w/w) were prepared, and slide crystallization

studies were performed. The addition of 10% w/w isopropyl myristate led to incorporation of higher

concentration of drug (up to 10% w/w) without separation from the dried adhesive blend, confirmed by

slide crystallization studies. The concentration of isopropyl myristate was limited to 10% w/w based on the

inactive ingredient guide provided by FDA (U.S. Food & Drug Administration, 2018). The incorporation

of liquid components (drug and permeation enhancer) in the silicone PSA led to a decrease in the viscosity
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 14

of the formulation blends. Therefore, the addition of a viscosity enhancer was considered to lower the

fluidity of the blend, enabling the formulation to be cast as a film. Previous literature demonstrates the

successful use of colloidal silicone dioxide as a viscosity enhancer (Enscore and Robert, 1985). Direct

addition of colloidal silicone dioxide to the adhesive blend led to the formation of indispersible lumps in

the blend. Hence, prior to addition, colloidal silicone dioxide was homogenized to a gel which could be

incorporated uniformly into the adhesive. The percentage of colloidal silicone dioxide remaining in the gel

after exposing it to the processing conditions of the patch was evaluated each time during preparation of an

adhesive blend, and the wet weight of gel to be added was back-calculated accordingly. Formulations F-C-

11 and F-C-12, containing 10% w/w colloidal silicone dioxide and devoid of isopropyl myristate, were

found to be the most suitable for the preparation of a transdermal patch. A loss in adhesive properties of the

dried matrix was observed in the formulations containing isopropyl myristate. Therefore, the use of

isopropyl myristate for drug in silicone blends was omitted. Colloidal silicone dioxide at 10% concentration

prevented the separation of drug for the dried adhesive matrix, while retaining the adhesive property of the

dried matrix and eliminated the need of adding isopropyl myristate.

Oleic acid and oleyl alcohol are also well-known chemical penetration enhancers that were included

in the PIB adhesive blends (Burton and Tata, 1999; Naik et al., 2000). Based on preliminary solubility

studies and existing literature recommendations, the concentration of oleic acid, oleyl alcohol was limited

to 5% w/w individually or 10% w/w in combination (Govil et al., 1993). On microscopical evaluation, a

uniform dispersion of drug as droplets was observed on for formulations 10POA, 10POAOH and

15POAOH (presented in Table 4). The matrix was found to be stable, with no apparent coalescence of the

droplets over a period of two weeks from casting on a slide. In case of 15POA, phase separation of drug

from the dried matrix was observed. The addition of oleic acid was successful in preventing the separation

of up to 10% w/w 4-benzylpiperidine, which led to a higher drug loading in the formulation. Formulations

10POA and 15POAOH were further investigated for the development of a transdermal patch of 4-

benzylpiperidine.
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 15

Drug in adhesive transdermal systems have three layers: backing film, a drug in adhesive matrix

layer and protective release liner. The backing film serves as the outer surface of a patch and prevents direct

contact of the patch formulation with the environment. Additionally, it provides mechanical support and

physical integrity to the transdermal system while also being compatible with the drug, adhesive and

excipients of the formulation. Release liners act as a protective layer for the transdermal patch system during

the product shelf life and act as substrates for the coating process therefore, they must be selected to provide

consistent release performance and inertness in the end-use application (Kandavilli et al., 2002). Adhesive

formulations can vary widely containing various additives, which can impact release performance and

adhesion properties. Considering the many factors involved, evaluation of several release liners and backing

is critical for the development of a transdermal patch (Govil et al., 1993; Wokovich et al., 2011). In the

present study, the final formulation blends selected (F-C-11 and F-C-12 silicone PSA based formulations;

10POA and 15POAOH PIB based formulations) were tested with a range of commonly used membranes,

used as release liners and backings. The material for release liner for the individual blends was chosen such

that the dried formulation would peel off easily from it, leaving no residue behind. On the contrary, the

membranes with great affinity for the formulation were chosen as backing membranes. Consecutively,

transdermal patches of these formulations were prepared with the most suitable combination of release liner

and backing (as described in Table 5). For the formulations containing silicone PSA, fluoropolymer coated

membranes were chosen as the release liner and polyester or polyethylene-based membranes were found to

have a greater affinity for the formulation and selected as backing. For the PIB based formulations, polyester

was chosen for the release liner and polyethylene as backing.

3.2. Drug in adhesive patch preparation

Drug in adhesive transdermal patches of 4-benzylpiperidine, with PIB and silicone PSAs were

developed successfully (summarized in Table 5). None of the patches developed showed separation of 4-

benzylpiperidine from the dried laminate or the formation of crystals when observed under an optical

microscope over two weeks. However, patches S2 and S4 had problems in terms of peeling, where the
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 16

laminate did not transfer entirely to the backing membrane and left residue on the release liner. As S1 had

higher concentration of drug than S3, patches S1, P1 and P2 were further tested for their drug permeation

profiles.

3.3. In vitro permeation

The average cumulative amount of 4-benzylpiperidine that permeated across dermatomed human

skin, over 48 hours, from S1 silicone adhesive patch, P1 drug-in-PIB adhesive patch and P2 drug-in-PIB

adhesive patch were found to be 559.2  79.4 µg/cm2, 748.1  36.0 µg/cm2, and 1608.5  53.4 µg/cm2

respectively. Patch P2 demonstrated significantly higher in vitro drug permeation compared to the other

two patches, as shown in Fig. 2. The average flux of 4-benzylpiperidine from S1, P1 and P2 was found to

be 11.2  1.4 µg/cm2/h, 19.9  1.2 µg/cm2/h, and 38.0  0.8 µg/cm2/h respectively, where the highest flux

was obtained from P2, as shown in Fig 3. The higher permeation of 4-benzylpiperidine from patch P2 can

be attributed to the higher drug loading (15% w/w) as well as the addition of two permeation enhancers,

oleic acid and oleyl alcohol. To obtain maximum delivery of 4-benzylpiperidine, patch P2 was selected as

the final transdermal patch of 4-benzylpiperidine.

3.4. Characterization of the optimized drug in adhesive patch

Patch P2 was further characterized as the final transdermal patch of 4-benzylpiperidine.

3.4.1. Determination of coat weight

The coating efficiency of a transdermal patch can be determined by measuring the coat weight of

different regions of the laminate. The variation in coat weight can be attributed to non-volatile components

in the adhesive blend (European Meedicines Agency, 2014). The average weight of patch P2, excluding the

weight of the release liner and backing membrane, was found to be 4.1 ± 0.6 mg, indicating uniformity in

coat weight throughout the laminate.

4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 17

3.4.2. Peel adhesion test

An ideal transdermal patch should peel off without causing delamination. Peel resistance is not

only dependent on the intrinsic adhesiveness of the PSA but is a complex process that involves the extension

and the bending of the patch matrix and the backing layer prior to separation. The force required to peel the

patch was kept consistent and as the value of peel adhesion is affected by the width of the sample, the size

of the patches were kept constant (Cilurzo et al., 2012). The average force required to peel patch P2 from

stainless steel was found to be 0.7  0.2 grams. There was no delamination on the stainless steel for the

tested transdermal patches.

3.4.3. Shear strength

Shear adhesion reveals the resistance of a transdermal patch to tangential stresses and, therefore,

the cohesion of the matrix (Cilurzo et al., 2012; Leong et al., 2003). In this study, the parallel force required

to pull a fixed area of the patch (15 cm2) from a standard flat surface (stainless steel) was tested. The average

time taken for the patch to drop from the test surface was found to be 53.8  7.9 seconds.

3.4.4. Tack Testing

The adhesion efficiency of a transdermal patch can be tested by tack evaluation methods, which

measure the force of debonding on application of a light pressure, for a short duration of time. A probe tack

test was employed in this study, where the force required to separate a probe from the adhesive surface of

a transdermal patch was measured. In this method, tack is expressed as the maximum value of the force

required to break the bond between the probe and transdermal patch after a brief period of contact (Cilurzo

et al., 2012). The average absolute positive force, average positive area and average separation distance,

recorded for six replicates, was found to be 80.4  11.9 g, 5.2  1.0 g/sec and 0.9  0.0 mm respectively.
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 18

4. Conclusion
Based on our results, the development of a transdermal drug-in-adhesive patch of 4-

benzylpiperidine was successful with silicone based and PIB based PSAs. Solubility and slide

crystallization studies demonstrated incompatibility of acrylates PSAs with the drug, hence, silicone and

PIB PSAs were selected for further patch development. The use of oleic acid, oleyl alcohol and isopropyl

myristate was found to be beneficial in increasing the loading of the drug in the patches as well as

permeation enhancers. In addition, colloidal silicone dioxide was successfully incorporated in the silicone-

based patches as a viscosity-building agent. Fluoropolymer coated membranes as the release liner and

polyester or polyethylene-based membranes as backing were chosen to develop the silicone PSA based

drug in adhesive patches. Among these S1 showed superior peeling performance and had higher drug

loading. For the PIB based formulations, polyester was chosen for the release liner and polyethylene as

backing. Patches S1, P1 and P2 were further evaluated for their drug permeation profiles across dermatomed

human skin. Higher delivery of drug from the two PIB based transdermal patches over the silicone-based

transdermal patch was obtained, and the P2 PIB based PSA transdermal patch was selected as the final

patch for further evaluation of adhesive properties. The final patch demonstrated uniformity in coat weight,

peel adhesion, tack test and shear strength. Further studies to evaluate the in vivo performance of the

optimized transdermal patch however will be required.

5. Tables

Table 1: Formulations prepared to test the solubility of 4-benzylpiperidine in the commonly used PSAs.

Drug (% w/w)
Adhesive Contents (mg)
5 10 20 40
Adhesive wet weight 1120.00 1120.00 1120.00 1120.00
Acrylate
Adhesive dry weight 565.60 565.60 565.60 565.60
(DURO-TAK 387-2287)
Amount of drug 29.77 62.84 141.40 377.07

Acrylate Adhesive wet weight 1120.00 1120.00 1120.00 1120.00

(DURO-TAK 387-2516) Adhesive dry weight 464.80 464.80 464.80 464.80
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 19

Drug (% w/w)
Adhesive Contents (mg)
5 10 20 40
Amount of drug 24.46 51.64 116.20 309.87

Adhesive wet weight 1120.00 1120.00 1120.00 1120.00

PIB
Adhesive dry weight 425.60 425.60 425.60 425.60
(DURO-TAK 87-6908)
Amount of drug 22.40 47.29 106.40 283.73

Adhesive wet weight 1120.00 1120.00 1120.00 1120.00

Silicone
Adhesive dry weight 672.00 672.00 672.00 672.00
(BIO PSA 7-4301)
Amount of drug 35.37 74.67 168.00 448.00

Table 2: Formulations prepared to further test the solubility of 4-benzylpiperidine in PIB and silicone

adhesives.

Drug (% w/w)
Adhesive Contents (mg)
5 10 20 40
Adhesive wet weight (mg) 1120 1120 1120 1120
PIB
Adhesive dry weight (mg) 425.60 425.60 425.60 425.60
(DURO-TAK 87-6908)
Amount of drug (mg) 8.69 13.16 17.73 20.05

Adhesive wet weight (mg) 1120 1120 1120 1120

Silicone
Adhesive dry weight (mg) 672 672 672 672
(BIO PSA 7-4301)
Amount of drug (mg) 13.71 20.78 28 31.66

Table 3: Formulations prepared with 4-benzylpiperidine in silicone PSA along with additives (isopropyl

myristate and colloidal silicon dioxide).

Excipients (% w/w)
Formulations Silicone Adhesive (dry Isopropyl Colloidal silicone
Drug
weight) myristate dioxide
F-C-4 10 72.5 10 7.5
F-C-5 5 82.5 5 7.5
F-C-6 5 77.5 10 7.5
F-C-7 12.5 70 10 7.5
F-C-8 10 75 5 10
F-C-9 12.5 72.5 5 10
F-C-10 10 77.5 5 7.5
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 20

F-C-11 10 80 0 10
F-C-12 5 85 0 10

Table 4: Formulations prepared with 4-benzylpiperidine in PIB PSA along with additives (oleic acid and

oleyl alcohol).

Formulations Excipients (% w/w)

Drug PIB Adhesive (dry weight) Oleic Acid Oleyl Alcohol
10POA 10 85 5 0
10POAOH 10 80 5 5
15POA 15 80 5 0
15POAOH 15 75 5 5

Table 5: Materials and conditions used to cast the drug in adhesive transdermal patches of 4-

benzylpiperidine, and the observations made post two weeks of casting.

Patch S1 S2 S3 S4 P1 P2
Drug 10 10 5 5 10 15
PIB
Adhesi
ve (% - - - - 85 75
dry
weight)
Silicon
e
Adhesi
80 80 85 85 - -
Compone ve (%
nts (% dry
w/w) weight)
Oleic
- - - - 5 5
Acid
Oleyl
Alcoho - - - - - 5
l
Colloid
al
10 10 10 10 - -
silicone
dioxide
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 21

Patch S1 S2 S3 S4 P1 P2
Fluoropoly Fluoropoly Fluoropoly Fluoropoly
Polyester Polyester
mer coated mer coated mer coated mer coated
side of side of
Release liner side of side of side of side of
Scotchpak Scotchpak
ScotchpakT ScotchpakT ScotchpakT ScotchpakT TM
9744 TM
9744
M
9741 M
9741 M
9741 M
9741

Matte Matte
Polyester CoTran™ Polyester CoTran™ surface of surface of
Backing side of 9718 side of 9718 Scotchpak Scotchpak
membrane ScotchpakT (Polyethyl ScotchpakT (Polyethyl TM
9723 TM
9723
M
9723 ene) M
9723 ene) (Polyethyl (Polyethyl
ene) ene)

A film of 15 mils in thickness was cast on the release liner and air dried in a
Drying Conditions fume hood for 2 min at room temperature, followed by drying at 75 °C for 15
min

Phase
separati      
on
Ease of
Observat      
peeling
ion after
2 weeks Residu
e on
     
release
liner

6. Figure Legends

Figure 1: Brightfield microscopic image showing (a) separation of drug (5% w/w) from dried

silicone adhesive and (b) formation of crystals in dried acrylate (DURO-TAK 387-2516) adhesive. Scale

bar = 50 µm

Figure 2: Demonstrates the in vitro permeation profile of 4-benzylpiperdine from the three patches

tested across human dermatomed skin over 48 hours. * Represents statistical difference (p < 0.05).
4-benzylpiperidine drug-in-adhesive matrix type transdermal patch 22

Figure 3: Demonstrates the average flux obtained from the three patches tested (S1, P1 and P2) at

the end of 48 hours. * Represents statistical difference when (p < 0.05).

7. Funding Information

These studies were supported by the Georgia Research Alliance based in Atlanta, Georgia by grant

number GRA.VL17.11 (Murnane and Banga - Multiple Principal Investigators) as well as by the National

Institute on Drug Abuse by grant number DA12970 (Blough - Principal Investigator).

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